A case-control study has previously been conducted (1986 - 1991) by the University of Buffalo Department of Social and Preventive Medicine. We are studying gene-environment and gene-gene interactions that determine a woman's risk of breast cancer. Genotyping for glutathione-S- transferase M1, CYP1A1, CYP2D6, CYP2E1, APOE, and N-acetyltransferase in postmenopausal women has been completed. The p53 mutational spectra will be determined in women with histologically proven cancer. Human sera is being examined for polychlorinated biphenyls. Postmenopausal women with incident, primary breast cancer (n=159) and controls (n=203) were genotyped for the NAT2 genetic polymorphism. This polymorphism governs acetylation of aromatic amines, which are mammary carcinogens in experimental studies. The NAT2 was not independently associated with breast cancer risk. However, the NAT2 genotype strongly modified the association of smoking with risk. Among slow acetylators, smoking 2, 10 and 20 years prior to the interview significantly increased breast cancer risk in a dose-dependent manner. Among rapid acetylators, smoking was not associated with breast cancer risk. These data indicate that smoking may be an important risk factor for breast cancer in susceptible populations. Postmenopausal women (n=216) and community controls (n=282) also were genotyped for the CYP1A1 and GSTM1 genetic polymorphisms. There was not overall association for these genotypes and breast cancer risk. However, the CYP1A1 genotype was found to be a risk factor in smokers, but only in persons who smoked less than 29 pack-years. The GSTM1 was found to be a risk factor in women under the age of 68. These data need to be confirmed and extended in additional ongoing studies. Statistical power to detect effects is limited by the small numbers of study subjects.